Noradrenergic neurons in the brain project into all parts of the neuraxis and regulate many functions of the nervous system, including memory, attention, emotion, and autonomic function. The norepinephrine transporter (NET) is primarily responsible for reuptake of norepinephrine (NE) into presynaptic nerve terminals, thus regulating both its transmission and homeostasis (1, 2). The NET belongs to a superfamily of Na+/Cl−-dependent transporters (3). The human NET (hNET) gene, spanning approximately 45 kb, is located on chromosome 16q12.2 (4). Genomic clones and cDNA encoding the human NET (hNET) have been isolated and characterized, thus making possible molecular investigation of regulatory mechanisms of NET gene expression (5).
Given the global role of NE in the CNS and PNS, dysfunction of the NE system may underlie various pathological conditions such as neurodegenerative, psychiatric, and endocrine disorders. Particularly, the gene encoding NET has been speculated to play a role in diverse psychiatric and autonomic disorders. For example, in patients suffering from major depression, the levels of NET, measured by brain imaging and binding techniques in post mortem brain samples, have been shown to be altered (6). The NET is reported to be a target of the tricyclic antidepressant drugs. In addition, the NET is reported to be a potential therapeutic target for treating posttraumatic stress disorder, social anxiety disorder, and eating disorder (7).
Several polymorphisms in the coding and non-coding regions of NET have been described. At present, there are about 20 known naturally occurring missense mutations in the coding region of hNET (10). These include several variants with impaired glycosylation and are decreased in surface expression, features that have been reported to influence the transporter function by altering its biosynthesis and trafficking (10, 11). An individual suffering from orthostatic intolerance, tachycardia, and elevated plasma NE levels recently has been reported to have a missense mutation (Ala457Pro) in the highly conserved transmembrane domain 9 of the NET (12). Further, a polymorphic region in the non-coding region was reported to be associated with anorexia nervosa (13).